This invention relates to the field of anti-type I interferon receptor antibodies, and more particularly to anti-type I interferon receptor antibodies that neutralize the anti-viral cytopathic effects of various type I interferons.
The type 1 interferons (IFNS) are cytokines that have pleiotropic effects on a wide variety of cell types. IFNs are best known for their anti-viral activity, but they also have anti-bacterial, anti-protozoal, immunomodulatory, and cell-growth regulatory functions. The type 1 interferons include interferon-xcex1 (IFN-xcex1) and interferon-xcex2 (IFN-xcex2). Human IFN-xcex1 (hIFN-xcex1) is a heterogeneous family with at least 23 polypeptides while there is only one IFN-xcex2 polypeptide (J. Interferon Res., 13: 443-444 (1993)). The hIFN-xcex1 subtypes show more than 70% amino acid sequence homology, and there is approximately 25% amino acid identity with hIFN-xcex2. The hIFNs-xcex1 and hIFN-xcex2 share a common receptor.
Three components of the hIFN-xcex1 receptor complex have recently been cloned. The cDNA for the first hIFN-xcex1 receptor (hIFNAR1) encodes a 63 kD receptor protein (reported in Uze et al., Cell, 60: 225-234 (1990)). This receptor undergoes extensive glycosylation, which causes it to migrate in gel electrophoresis as a much larger 135 kD protein. The second interferon receptor, hIFNAR2 (hIFN-xcex1xcex2R long), is a 115 kD protein which mediates a functional signaling complex when associated with hIFNAR1 (reported in Domanski et al., J. Biol. Chem., 270: 21606-21611 (1995)). The third hIFN-xcex1 receptor, an IFN-xcex1/xcex2 receptor (hIFN-xcex1xcex2R short), is a 55 kD protein that can bind to type 1 hIFNs but cannot form a functional complex when associated with hIFNAR1 (reported in Novick et al., Cell, 77: 391-400 (1994)). This IFN-xcex1/xcex2 receptor appears to be an alternatively spliced variant of hIFNAR2.
The unprocessed hIFNAR1 expression product is composed of 557 amino acids including an extracellular domain (ECD) of 409 residues, a transmembrane domain of 21 residues, and an intracellular domain of 100 residues as shown in FIG. 5 on page 229 of Uze et al., supra. The ECD of IFNAR1 is composed of two domains, domain 1 and domain 2, which are separated by a three-proline motif. There is 19% sequence identity and 50% sequence homology between domains 1 and 2 (Uze et al., supra). Each domain (D200) is composed of approximately 200 residues and can be further subdivided into two homologous subdomains (SD100) of approximately 100 amino acids.
Cytokine receptors have been categorized into two classes based on the distribution of cysteine residues. The class 1 cytokine receptor family includes receptors for human growth hormone (hGHR), erythropoietin, IL-3 and IL-4, while the class 2 cytokine receptor family includes the IFNxcex3 receptor, tissue factor, CRF2-4 and IL-10 receptors. Sequence analysis of the hIFN-xcex1 receptors shows that they are related to the class 2 cytokine receptor family.
Through the use of IFNAR1 gene knockout mice, IFNAR1 has been shown to be essential for the response to all type 1 IFNs (Muller et al., Science, 264: 1918-1921 (1994); Cleary et al., J. Biol. Chem., 269: 18747-18749 (1994)) and for the mediation of species-specific IFN signal transduction (Constantinescu et al., Proc. Natl. Acad. Sci. USA, 91: 9602-9606 (1994)).
Benoit et al., J. Immunol., 150: 707-716 (1993) reported an anti-IFNAR1 mAb, 64G12, that was found to inhibit the binding of IFN-xcex12 (IFN-xcex1A) and IFN-xcex18 (IFN-xcex1B) to Daudi cells and to inhibit the antiviral activity of IFN-xcex12, IFN-xcex2 and IFN-xcfx89 (IFN-xcex1II1) on Daudi cells. Benoit et al. also reported that 64G12 recognizes an epitope present in domain 1 of IFNAR1. Eid and Tovey, J. Interferon Cytokine Res., 15: 205-211 (1995) reported that 64G12 cannot immunoprecipitate cross-linked IFN-xcex12-receptor complexes from Daudi cells.
In one aspect, the invention provides an anti-IFNAR1 monoclonal antibody that inhibits the anti-viral activity of a first type I interferon and does not inhibit the anti-viral activity of a second type I interferon.
In another aspect, the invention provides an anti-IFNAR1 monoclonal antibody that inhibits anti-viral activity of a first type I interferon and does not inhibit the anti-viral activity of IFN-xcex12.
In still another aspect, the invention provides an anti-IFNAR1 monoclonal antibody that inhibits anti-viral activity of a first type I interferon and does not inhibit the anti-viral activity of IFN-xcex18.
In yet another aspect, the invention provides an anti-IFNAR1 monoclonal antibody that inhibits anti-viral activity of a first type I interferon and does not inhibit the anti-viral activity of IFN-xcex1II1.
In a further aspect, the invention provides an anti-IFNAR1 monoclonal antibody that inhibits anti-viral activity of a first type I interferon and does not inhibit the anti-viral activity of IFN-xcex2.
In an additional aspect, the invention provides an anti-IFNAR1 monoclonal antibody that inhibits the anti-viral activity of a first type I interferon and does not inhibit the anti-viral activity of a second type I interferon selected from the group consisting of IFN-xcex12, IFN-xcex18, IFN-xcex1II1, and IFN-xcex2.
The invention also encompasses an anti-IFNAR1 monoclonal antibody that binds to one or more amino acids in situ in the sequence of amino acids 244-249 of IFNAR1, and binds to one or more amino acids in situ in the sequence of amino acids 291-298 of IFNAR1.